Breakthrough Acute Necrotizing Invasive Fungal Rhinosinusitis by Alternariaalternata in a Patient with Acute Lymphoblastic Leukemia on Anidulafungin Therapy and Case-Based Literature Review.

Alternaria spp. have emerged as opportunistic pathogens particularly in immunosuppressed patients. A case of a breakthrough acute invasive fungal rhinosinusitis (AIFRS), caused by Alternaria alternata, is reported in a patient with acute lymphoblastic leukemia (ALL) on anidulafungin therapy, who was successfully treated with liposomal amphotericin B and surgical intervention. To date, 20 cases of AIFRS due to Alternaria spp. have been described, 19 in the USA and 1 in Chile, making this case report the first case of AIFRS due to Alternaria in Europe. The patients had median (range) age 25 (2-56) years (65% female), almost all of them (19/20) with hematological diseases and severe neutropenia (8-41 days pre-infection). Amphotericin B was the most frequently used antifungal agent, either alone or in combination. In all of the cases, systemic antifungal therapy was combined with surgery. Despite stabilization or improvement of the AIFRS, mortality was 38% (5 days to 8 months post-surgical debridement) due to their underlying disease or other infections without sign of AIFRS at autopsy.

TLR4 and pSTAT3 Expression on Circulating Tumor Cells (CTCs) and Immune Cells in the Peripheral Blood of Breast Cancer Patients: Prognostic Implications.

TLR4 and pSTAT3 are key players in cancer inflammation and immune evasion; however, their role in the peripheral blood (PB) is largely unexplored. Herein we evaluated their expression in the circulating tumor cells (CTCs) and peripheral-blood mononuclear cells (PBMCs) of patients with early (n = 99) and metastatic (n = 100) breast cancer (BC). PB samples obtained prior to adjuvant and first-line therapy, were immunofluorescently stained for Cytokeratins/TLR4/pSTAT3/DAPI and analyzed via Ariol microscopy. TLR4+ CTCs were detected in 50% and 68% of early and metastatic CTC-positive patients, respectively, and pSTAT3+ CTCs in 83% and 68%, respectively. In metastatic patients, CTC detection was associated with a high risk of death (HR: 1.764, p = 0.038), while TLR4+ CTCs correlated with a high risk of disease progression (HR: 1.964, p = 0.030). Regarding PBMCs, TLR4 expression prevailed in metastatic disease (p = 0.029), while pSTAT3 expression was more frequent in early disease (p = 0.014). In early BC, TLR4 expression on PBMCs independently predicted for high risk of relapse (HR: 3.549; p = 0.009), whereas in metastatic BC, TLR4+/pSTAT3- PBMCs independently predicted for high risk of death (HR: 2.925; p = 0.012). These results suggest that TLR4/pSTAT3 signaling on tumor- and immune-cell compartments in the PB could play a role in BC progression, and may hold independent prognostic implications for BC patients.

Predicting outcome in higher-risk myelodysplastic syndrome patients treated with azacitidine.

5-Azacitidine (5-AZA) is widely used for the treatment of higher-risk myelodysplastic syndromes. However, response and survival rates vary considerably, while indicated treatment duration remains undefined. For these reasons, factors determining response and survival are of major importance. Clinical, morphological, flow cytometry, cytogenetic and molecular factors are discussed in this review. Biomarkers predictive of response and prognosis, as well as their link to the mode of action of 5-AZA are also addressed, shifting the focus from clinical practice to investigational research. Their use could further improve prognostic classification of 5-AZA treated higher-risk myelodysplastic syndromes in the near future.

Lay abstract Myelodysplastic syndrome is a disorder in which patients have dysfunctional blood cells. The only chance of curing patients with high-risk myelodysplastic syndrome (HR-MDS) is allogeneic stem cell transplantation. However, most HR-MDS patients are not young or fit enough to receive such a toxic treatment. For these patients, hypomethylating drugs such as 5-azacitidine (5-AZA) and decitabine are preferable treatments. These drugs work by reducing the number of molecules known as methyl groups that are attached to DNA, which can lead to cell death. About half of patients respond to it, and those who do respond, survive longer than those who do not. In addition, 5-AZA delays disease progression from HR-MDS to acute myeloid leukemia, a type of blood cancer, and may help patients who do not improve to live longer. However, 5-AZA has side effects that can be hard to bear, such as an increased need for red blood cells and/or platelet transfusions. For this reason, it would be good to predict the clinical and biological factors associated with either response or final outcome following treatment. In this manuscript, we attempt to summarize current knowledge on this topic.

Solitary extramedullary plasmacytoma of the nasopharynx: The role of flow cytometry.

Extramedullary plasmacytoma (EMP) represents a distinct yet rare entity among the plasma cell neoplasms. Given its rarity, no therapeutic consensus has been met. We report the case of a 57-year-old man with a one-year history of nasal congestion and occasional dyspnoea. Imaging showed a hypermetabolic mass in the right nasopharynx extending backward towards the adjacent oropharynx, infiltrating the epiglottis. As incisional biopsy showed histologic and immunophenotypic features consistent with plasma cell neoplasm, whereas the possibility of a marginal zone lymphoma with plasmacytic differentiation was included in the differential diagnosis. A final diagnosis of EMP was reached by using flow cytometry (FC) of a cell suspension from the neoplastic tissue. The patient received local radiotherapy (RT) which resulted to complete remission. In conclusion, flow cytometry might serve as an auxiliary method in cases where immunohistochemistry cannot differentiate between a plasma cell dyscrasia and a B-non-Hodgkin lymphoma. In cases of an established diagnosis of solitary nasopharyngeal EMP RT represents an excellent treatment modality offering prolonged disease-free survival.

Optimization of the Enrichment of Circulating Tumor Cells for Downstream Phenotypic Analysis in Patients with Non-Small Cell Lung Cancer Treated with Anti-PD-1 Immunotherapy.

The current study aimed at the optimization of circulating tumor cell (CTC) enrichment for downstream protein expression analyses in non-small cell lung cancer (NSCLC) to serve as a tool for the investigation of immune checkpoints in real time. Different enrichment approaches-ficoll density, erythrolysis, their combination with magnetic separation, ISET, and Parsortix-were compared in spiking experiments using the A549, H1975, and SKMES-1 NSCLC cell lines. The most efficient methods were tested in patients (n = 15) receiving immunotherapy targeting programmed cell death-1 (PD-1). Samples were immunofluorescently stained for a) cytokeratins (CK)/epithelial cell adhesion molecule (EpCAM)/leukocyte common antigen (CD45), and b) CK/programmed cell death ligand-1 (PD-L1)/ indoleamine-2,3-dioxygenase (IDO). Ficoll, ISET, and Parsortix presented the highest yields and compatibility with phenotypic analysis; however, at the patient level, they provided discordant CTC positivity (13%, 33%, and 60% of patients, respectively) and enriched for distinct CTC populations. IDO and PD-L1 were expressed in 44% and 33% and co-expressed in 19% of CTCs. CTC detection was associated with progressive disease (PD) (p = 0.006), reduced progression-free survival PFS (p = 0.007), and increased risk of relapse (hazard ratio; HR: 10.733; p = 0.026). IDO-positive CTCs were associated with shorter PFS (p = 0.039) and overall survival OS (p = 0.021) and increased risk of death (HR: 5.462; p = 0.039). The current study indicates that CTC analysis according to distinct immune checkpoints is feasible and may provide valuable biomarkers to monitor NSCLC patients treated with anti-PD-1 agents.

Clinical Relevance of Immune Checkpoints on Circulating Tumor Cells in Breast Cancer.

The role of CD47 and PD-L1 expression on circulating tumor cells (CTCs) remains unclear, and it is currently unknown whether their distribution varies between the blood and tumor tissue in breast cancer (BC). In this study, CD47 and PD-L1 expression was investigated a) on peripheral blood mononuclear cell (PBMC) cytospins from early (n = 100) and metastatic (n = 98) BC patients, by triple immunofluorescence for CD47/PD-L1/Cytokeratins, and b) on matched primary and/or metastatic tumor tissue from CTC-positive patients using immunohistochemistry. CD47+and/orPD-L1+ CTCs were detected in 11%, 16.9%, and 29.6% of early, recurrent, and de novo metastatic patients (p = 0.016). In metastatic disease, CD47highand/orPD-L1high CTCs were associated with disease progression (p = 0.005) and shorter progression-free survival (PFS) (p = 0.010), and independently predicted for an increased risk of relapse (HR: 2.719; p = 0.008) and death (HR: 2.398; p = 0.034). PD-L1 expression rates differed between CTCs and tissue tumor cells and between peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) (positive concordance of 3.8% and 4%, respectively). CD47 expression also differed between CTCs and tumor cells (positive concordance of 11.5%). In conclusion, CTCs expressing CD47 and PD-L1 have independent poor prognostic implications in metastatic BC, indicating a potential role of innate and adaptive immune evasion mechanisms in their metastatic potential. The clinical value of the parallel assessment of the peripheral and local immune response merits further evaluation in BC.

Acute Abdominal Pain Assessment in the Emergency Department: The Experience of a Greek University Hospital.

BACKGROUND: Acute abdominal pain (AAP) is a common symptom in the emergency department (ED). Because abdominal pain can be caused by a wide spectrum of underlying pathology, evaluation of abdominal pain in the ED requires a comprehensive approach, based on patient history, physical examination, laboratory tests and imaging studies. The aim of this study was to investigate predictive factors for admission to the hospital in patients who presented to the ED with AAP as the main symptom. METHODS: This prospective observational study enrolled 125 patients who presented with AAP in the ED of the Patras University Hospital in western Greece. The sample of patients who enrolled in the study was representative of patients who receive care in this academic institution. All patients underwent clinical examination, laboratory testing and radiological assessment. Clinical and laboratory data were analyzed in an attempt to identify clinical or laboratory factors predicting hospital admission. RESULTS: Based on clinical, laboratory and radiologic evaluation, 37.6% of patients enrolled in the study were admitted to the hospital, whereas 62.4% were not admitted. Compared to patients who were not admitted, patients admitted to the hospital had higher age and significantly higher inflammatory markers, white blood count and C-reactive protein (CRP). Binary logistic regression analysis showed that abnormal imaging findings (odds ratio (OR) = 6.47, 95% confidence interval (CI): 2.11 - 19.77, P < 0.001) and elevated serum CRP levels (OR = 6.24, 95% CI: 2.16 - 18.03, P < 0.001) were significant predictive factors for hospital admission. CONCLUSIONS: Assessment of AAP remains a challenging problem in the ED. Comprehensive history combined with detailed clinical examination, appropriate laboratory testing and radiologic imaging facilitates effective assessment of patients who present in the ED with AAP and guides the decision to admit patients to the hospital for further care.

Use of Sodium Bicarbonate in Cardiac Arrest: Current Guidelines and Literature Review.

The aim of the review was to summarize the literature over the last 25 years regarding bicarbonate administration in out-of-hospital cardiac arrest. A PubMed search was conducted using the terms "bicarbonates" and "cardiac arrest", limited to human studies and reviews published in English (or at least with a meaningful abstract in English) in the last 25 years. Clinical and experimental data raised questions regarding the safety and effectiveness of sodium bicarbonate (SB) administration during cardiac arrest. Earlier advanced cardiac life support (ACLS) guidelines recommended routine bicarbonate administration as part of the ACLS algorithm, but recent guidelines no longer recommend its use. The debate in the literature is ongoing, but at the present time, SB administration is only recommended for cardiac arrest related to hypokalemia or overdose of tricyclic antidepressants. Several studies challenge the assumption that bicarbonate administration is beneficial for treatment of acidosis in cardiac arrest. At the present time, there is a trend against using bicarbonates in cardiac arrest, and this trend is supported by guidelines published by professional societies and organizations.